Cis-Pt(NH3)2Cl2 and related compounds are among the most promising anti-tumor drugs developed recently. This drug, which has been shown to be active against a wide range of tumors, is currently undergoing Phase II clinical tests at the National Cancer Institute. The action of cis-Pt(NH3)2Cl2 is believed to lie in the drug's apparent ability to suppress DNA replication. The actual mode of molecular interaction is not precisely known, but is believed to involve the formation of interstrand or intrastrand cross-links within a DNA molecule. Many theories of the Pt/DNA interaction have been proposed; most involve the formation of strong covalent bonds between platinum and certain nitrogen atoms of the purines. In order to get a better appreciation for the molecular nature of DNA/Pt interaction, we feel that it is essential to first know these structural details at a more basic level; i.e., at the nucleotide or oligonucleotide level. The purpose of this proposal is to prepare and determine the structures of various Pt-nucleotide and Pt-dinucleotide complexes by X-ray diffraction methods. The Pt-dinucleotide complexes in particular should be extremely useful as models for testing the feasibility of intra-strand cross-link formation across two adjacent bases of a DNA strand. Eventually we hope to extend our work to more complex systems such as platinum-trinucleotide complexes or mixed platinum-oligonucleotide systems. We hope that the knowledge gained from these X-ray structural studies will be useful in (a) understanding the Pt/DNA interaction at a molecular level and (b) helping the design of derivatives of cis-Pt(NH3)2Cl2 which might have more favorable physiological properties. BIBLIOGRAPHIC REFERENCES: "The Structure of the (Platinum(ethylenediamine)(guanosine)2)2ion Cation" by R.W. Gellert and R. Bau, J. Amer. Chem. Soc., 97, 7379 (1975). "Structures of Cd(5'-CMP)(H2O) and the (Pt(en) (guanosine)2)2 ion Cation", by R. Bau, R.W. Gellert and J.K. Shiba, Proc. 7th Int. Conf. on Organometal. Chem., 238 (1975).